Foreword

While it is still a different era than anyone born before 1965 can remember, much is left to be done to optimize care of transgender youth. Whether to include Gender Dysphoria as a psychiatric diagnosis in the next version of the Diagnostic and Statistical Manual of Psychiatric Diseases (DSM) remains controversial. This is reminiscent of 1973, when homosexuality was removed from the DSM as a psychiatric disease. Only within the past 5 years has Gender Identity Disorder been expunged from the DSM and replaced with Gender Dysphoria , which had helped to soften the view of this diagnosis being seen as a psychological illness. Previously, transgender youth were only able to obtain insurance coverage for mental health services for their diagnosis of Gender Dysphoria . Neither medical therapy to suppress unwanted natal puberty nor gender-affirming hormones were covered under this diagnosis. The most expensive treatments of gender-affirmative care, including “top surgery” in transgender men and feminizing genitoplasties in transgender women were limited to those who could afford high out-of-pocket expenses. This created a privileged environment for those who could afford medical and surgical transition. Thankfully, more insurance companies are recognizing the medical and surgical necessity of these treatments to alleviate gender dysphoria and its associated comorbid depression and anxiety.

It has not been an easy road to the current state of caring for transgender youth. Current guidelines have recommended delaying medical transition until the age of 16 and, until then, mental health counseling was the mainstay of treatment. If transgender youth have to wait until age 16 for medical intervention, little can be done for trans men who complete full female puberty, with their final height unable to be influenced by medical treatment and a need for a complicated mastectomy to remove breast tissue. If intervention could be done earlier, weekly testosterone could stop menses and induce masculinization including virilizing the body, face and scalp hair, muscle development, and changes in fat distribution. Trans women who reach 16 years without intervention may develop a full male voice, facial hair, or Adam’s apple. These young patients would have benefited from the typical antiandrogen treatment of spironolactone to suppress the pilosebaceous unit associated with hair growth, as well as high-dose oral estrogen in order to suppress serum testosterone levels to the low physiologic female range. Pushing the estrogen dose to these high doses increases the risk of thromboembolism; however, without this type of dosing, virilization may continue, necessitating some to pursue expensive electrolysis while others may be dissatisfied with their breast growth prompting them to seek augmentation surgery.

There are many medical and surgical consequences associated with delay in treatment, but the greatest morbidity in adolescents is the consequence associated with the persistent disconnect between their gender identity and their ability to live in their affirmed gender social role. One statistic says it best: there is a 41% risk of suicide attempt in young adults who are 18 to 24 years old if their affirmed identity is not supported or treated psychologically or medically. When one of the pioneers of transgender medicine, Dr. Louis Gooren, from Amsterdam’s Gender Clinic retrospectively studied the causes of death of approximately 1200 individuals from his cohort, he found that the risk of mortality was 51% higher than the general population. The psychological causes, mainly suicide and drug abuse, were unrelated to the use of hormonal therapy. All patients in this cohort had started hormonal treatment as adults. The authors concluded that delayed treatment resulted in patients feeling unable to fit in physically and socially and this played a significant role in the cause of death of many of the patients studied. These data provided the impetus for the Dutch to try an earlier more effective treatment, now affectionately termed “the Dutch protocol” on which our current approach to transgender youth is based.

Norman Spack, MD

Introduction

Since ancient times there has been recognition of gender variance. Classical mythology abounds with examples of the gender variant; the most well-known is the Greek Olympian god Dionysus, who was male in figure but frequently described as androgynous. Hermaphroditus, the son of Hermes and Aphrodite, fell in love with the water nymph Salmacis, who had their physical forms joined to form an androgynous being. Agdistis, a multigendered and powerful god, was created by the mating of Zeus with Mother Earth. In more modern times, the acceptance and recognition of gender nonconformity has been increasing at an unprecedented rate, with subsequent expansion of dedicated medical and mental health specialists all over the world. Accurate estimates of the number of people defining themselves as gender variant is unknown but historically varies from 1 in 4000 to 1 in 50,000, but the actual prevalence is likely to be much higher. It is currently estimated that there are about 700,000 adults in the United States who are transgender, although the true number is not currently known.

Cross-sex hormonal therapy for adults has been available for many years but its use is not always able to completely alter the natal physiologic changes that occurred at the time of puberty, leading many patients to seek surgical procedures to help them with their transition. Suppressive therapy to prevent unwanted and often distressing secondary sex characteristics with gonadotropin-releasing hormone (GnRH) agonists to block the natal puberty was first described by the Dutch in 1998 but is now widely used and part of the standards of care for adolescents. The incorporation of these agents, casually called “blockers,” has revolutionized the care of transgender adolescents, allowing them to much more easily pass in society as their self-identified gender. Available evidence suggests that hormonal transition is an effective treatment for gender dysphoria, and blockers have become a mainstay treatment for younger patients.

The model for transgender adolescent care in the United States was first established by our group at Boston Children’s Hospital based on practices pioneered by Amsterdam’s Gender Clinic. In standard practice, children are given a GnRH agonist for pubertal blockade in early puberty followed by consideration for cross-sex hormones at age 16 years and gender affirmation surgery after age 18. While practices for cross-sex hormone therapy have mostly been extrapolated from adult transgender care pathways, the timing of puberty in adolescents requires special consideration. Puberty onset varies in each individual and may be less apparent in natal boys as testicular enlargement without outward androgenic signs is the first sign of puberty and is often unrecognized by parents. Additionally, arresting puberty causes a return to a prepubertal growth rate and proceeding with or altering the dosing regimen of cross-sex hormones may need to be hastened in order to avoid the development of poor bone density and to take into account desired adult height. If the above-mentioned standard practice is followed, (implementing cross-sex hormones closer to 16 years of age), adolescents on GnRH agonists may suffer from remaining in a prepubertal body while their peers undergo their normally timed natal puberty.

This chapter will review the current hormonal therapy options available for the adolescent with particular emphasis on pubertal blockade and subsequent gender-affirming hormone therapy.

Guidelines and Requirements for Hormone Therapy

The approach to treating children and adolescents is complex, as available evidence suggests that the majority of children who behave in a “cross gender role” prepubertally may later identify with their natal gender during or after adolescence, a phenomenon known as “desistance.” Looking retrospectively it appears that there is a link between the intensity of the gender dysphoria and continued identification into adolescence and adulthood. That is, children who are highly persistent, insistent, and consistent in their identity are likely to be stable in their trans-identity into adulthood. Additionally, when the physical signs of puberty appear, the dysphoria worsens. Despite this knowledge, being able to accurately identify these “persistent” children during the prepubertal phase is a challenge. The decision to initiate hormone therapy, therefore, has been recommended to be not only measured and multidisciplined, but also timed to start after the first signs of puberty.

Similar to the adult patient, guidelines for the diagnosis and treatment of adolescents are available from both the Endocrine Society and the World Professional Association for Transgender Health (WPATH) standards of care, both of which rely on the DSM for guidance in establishment of the diagnosis. A skilled mental health professional must first make the diagnosis of Gender Dysphoria . Rationale for this recommendation is that it is important to be able to identify and parse out other conditions that may obscure the correct diagnosis as well as ensuring that there is continued mental health support during social and medical transition.

The DSM 5 has revised its nomenclature, replacing the diagnosis Gender Identity Disorder with the term Gender Dysphoria . This emphasizes that the clinically important element is distress surrounding the condition, while making the distinction that gender nonconformity is not itself a disorder. As an example, hormone therapy may provide significant relief to an individual who has gender dysphoria but not necessarily to someone who has gender nonconformity without distress. While it is controversial and potentially stigmatizing to have gender-related issues fall under the realm of mental health, advocates point out that its inclusion allows for medical and mental health treatment to be covered by insurance using this diagnosis. The International Classification of Diseases, 11th edition (ICD 11) will likely use the term Gender Incongruence and move this diagnosis out of the chapter of mental and behavioral disorders.

The administration of gender-affirming exogenous hormones is considered essential to the treatment of gender dysphoria by current standards of care. Hormone therapy must be balanced based on its risk/benefit ratio, the patient’s coexisting medical conditions, social concerns, and cost. The efficacy of hormonal therapy has been well studied and documented, although many of these studies include patients who have also undergone gender affirmation surgery. A meta-analysis conducted by Murad and colleagues of 28 studies of both hormone therapy as well as gender affirmation surgery found significant improvement in gender dysphoria, quality of life, and psychological symptoms after therapy, albeit from relatively low quality studies. One prospective study assessing 57 patients at varying time points following treatment for diagnosed Gender Dysphoria found that the most substantial decrease in psychoneurotic distress occurred after the initiation of cross-sex hormones. The corollary is that the risk of suicidality is decreased with better access to medical treatment.

The rationale for hormonal therapy is based on the observation that young prepubertal children are typically gender-identified by their clothing, mannerisms, and activities. The ability to prevent the physical characteristics that typically associate with what is feminine or masculine would allow for the trans-identifying individual to avoid the permanent secondary sexual characteristics that are often distressing. For the adolescent in early puberty there is the potential for two phases for hormone therapy: the suppression of natal hormones to prevent the secondary sexual characteristics of the assigned gender, and the initiation of gender-affirming or “cross-sex” hormones.

Guidelines for GnRH agonist treatment as outlined by the Endocrine Society ( Table 6.1 ) state that adolescents should fulfill criteria for a diagnosis of Gender Dysphoria (DSM 5) and that they should be in early puberty, as the emotional reaction to physical changes of puberty has diagnostic value. Additionally, they must not have a psychiatric comorbidity that interferes with diagnosis or treatment. They must also have adequate psychological and social support and they must demonstrate understanding of the purpose of the GnRH agonist and its role in the larger picture of gender transition. Current guidelines advocate for use of GnRH agonists in all adolescents prior to cross-sex hormone administration; however, this may not be required in late-presenting adolescents, especially trans men who can effectively virilize with exogenous testosterone treatment. As previously mentioned, GnRH agonist therapy can be expensive and it is currently covered in a limited number of states.

Per the guidelines, an adolescent should fulfill all of the above criteria and have the capacity to make an informed decision to receive gender-affirming hormones. It is important to note that since publication of the 2011 guidelines, the age of initiation of gender-affirming hormones has steadily decreased, with some centers starting as young as 12 or 13 years of age in selected cases. In our practice, the youngest we typically start cross hormone therapy is 14 years. The newest guidelines were published in 2017 and do not restrict providers to a minimum age. It is also worth noting that although there is a stipulation for adults to have “real life experience” as living in their affirmed gender (they live full-time in this gender), there is no such recommendation specific to the adolescent for either puberty blocker treatment or cross-sex hormone administration.

As the field of transgender medicine has evolved, it has become evident that not every adolescent has a “classic” presentation of Gender Dysphoria ; they may be quite comfortable with their current state of physical development but still maintain a strong desire to move forward with GnRH agonist or gender-affirming hormones. This is something that should not necessarily preclude hormonal therapy, particularly as GnRH agonists are reversible. When assessing a gender nonconforming child or adolescent with dysphoria who desires a neutral gender, their identity as such should not be overlooked. The withholding or delay of therapy is by itself an unfavorable option with potentially severe psychosocial and permanent physical health consequences. These scenarios can be quite challenging if the adolescent and parents are not in agreement, which emphasizes the need for a multidisciplinary team approach to caring for these patients.

Considerations in the Adolescent Patient Population

Providing medical treatment to the transgender adolescent carries an increased complexity compared to the treatment of adults. Family dynamics and need for guardian consent in the absence of clear factors to identify those youth who will persist in their affirmed gender identity must be balanced within the co-occurrence of an unwanted natal puberty, which if left untreated, can worsen gender dysphoria. Transgender youth often feel that they are suffering from precocious puberty of an unwanted natal puberty and delayed puberty of their self-affirmed gender. Medical providers also struggle with the lack of long-term safety data on current standards in medical care of transgender youth in an era of evidence-based medicine. Evolving practices in caring for transgender youth include meeting patients’ needs as the prevalence of nonbinary gender identity increases, where adolescents may exhibit gender fluidity. Additionally, increasing medical complexity, such as the increasing prevalence of autism spectrum disorder in transgender youth, can complicate the assessment of gender identity and obtainment of assent for treatment.

Newer publications have highlighted the protective role that parental support and acceptance may have on the development of mental health disorders and high-risk behaviors such as substance abuse in transgender youth. Parental support has been associated with significantly higher satisfaction in life and fewer depressive symptoms including a lower rate of suicidal ideation. It is widely known that suicide attempts in transgender youth are alarmingly high. In one study of trans youth 12 to 24 years of age, nearly one-fourth had mild-to-moderate depression and one-tenth had severe to extreme depression. Half of the youth had reported contemplating suicide and one-third had attempted suicide at least once. These rates have been supported by other studies at other centers caring for transgender children and adolescents. In addition, high-risk behaviors are prevalent among trans youth with many reporting alcohol, tobacco, marijuana, and other illicit drug use. Transgender youth require ongoing monitoring for depressive symptoms as they may be at risk for developing suicidal ideation as they get older, which can be independent of behavioral and emotional problems.

Ethical issues in treating adolescents include respecting an adolescent’s autonomy and right to assent to treatment while requiring the consent of his or her parents or guardians for moving forward with medical treatment. Providers struggle with how best to proceed with treatment in cases where one or both parents are not in support of the diagnosis of gender dysphoria and/or certain treatments for medical transition. Very challenging cases may require the consult of an ethics committee or involvement of a legally appointed guardian to advise on the child’s best interest.

Adequate consent for gender affirming hormones must include the unknown long-term risks to fertility. Increased awareness for the need for adequate fertility education, access to care, and treatment options for this population is growing. This was previously thought to be an issue concerning only adults, but children are significantly affected as well. Data from the literature on central precocious puberty have shown that GnRH agonist treatment confers no risk to fertility. Fertility preservation options will vary based on the pubertal stage at the time of gender-affirming hormone initiation. Families should be offered a consultation with a fertility specialist if available in the medical community and future studies are needed to clarify how opinions on parenthood and fertility vary as the adolescent ages. We have data that show that transgender adults who have pursued parenthood have been able to reimagine having a child under different terms and have resisted accepting current cultural norms of parenthood.

Finally, while there is relative consensus on how to support and treat adolescents, social transition in prepubertal children is more controversial. Increasing attention has been given to the role of the provider in advising parents of transgender youth and support has been mounting for a gender affirmative model. Some argue that prepubertal children should be treated to reduce gender dysphoria and increase acceptance of their assigned sex. Newer studies show the positive effects that are associated with supporting the affirmed gender of gender nonconforming prepubertal children. These studies show that those children who are allowed to socially transition have similar rates of depression and only minimally increased rates of anxiety when compared to cischildren of the same age. Further prospective studies are needed.

Pubertal Suppression

The prevention of the secondary sexual characteristics of an individual’s natal gender has become standard of care in the treatment of gender nonconforming individuals and is recommended by both WPATH and the Endocrine Society in the treatment of these patients, and has been published as part of the Dutch protocol. This relatively simple intervention has revolutionized the experience for many individuals, allowing them to avoid many of the secondary sexual characteristics of their biologic sex, thus giving them in essence a “tabula rasa” for the hormone therapy of their affirmed gender and allowing them to “pass” in society more easily in their affirmed gender, which has been associated with better psychological adjustment and outcomes in adulthood.

While the benefit of GnRH agonists is the reversibility of the treatment, medical providers and psychologists caring for transgender youth share concerns about the psychological impact of removing sex hormones via GnRH agonist therapy during a critical time of sex steroid exposure in adolescence. However, proponents of GnRH agonist therapy assert that this treatment offers much needed relief from the development of natal puberty and allows the adolescent, their family, and mental health and medical providers additional time to explore the adolescent’s gender identity, extent of dysphoria, and appropriate treatment plan.

From a physiologic standpoint, the hypothalamic-pituitary-gonadal (HPG) axis undergoes a period of quiescence in childhood and is subsequently reactivated at the onset of puberty. This reactivation is due to a complex interplay of genetic, environmental, and nutritional factors. Puberty is initiated by the release of tonic inhibition of pulsatile secretion of GnRH from the hypothalamus in the setting of increased stimulatory factors on GnRH secretion. These pulses cause release of luteinizing hormone (LH) and follicular-stimulating hormone (FSH) from the pituitary gland. These pituitary gonadotropins then circulate to the gonads and stimulate production of sex steroids, predominantly estrogen from the ovary and testosterone from the testes ( Fig. 6.1 ).

The hypothalamus secretes gonadotropin-releasing hormone, which during puberty signals the pituitary gland to release luteinizing hormone (LH) and follicular-stimulating hormone (FSH) . These gonadotropins then signal the gonads (either testes or ovaries) to make sex steroids. The gonadotropin-releasing hormone (GnRH) agonist works at the level of the hypothalamus and pituitary gland, causing a downregulation of GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes, thus decreasing levels of LH and FSH.

(Adapted from Du Plessis SS, Cabler S, McAlister DA, Sabanegh E, Agarwal A. The effect of obesity on sperm disorders and male infertility. Nat Rev Urol. 2010;7:153–161.)

With the use of GnRH agonists, there is loss of endogenous GnRH pulsatility. GnRH agonists bind to the GnRH receptor, initially stimulating the pituitary gonadotrophs to produce and secrete LH and FSH and downstream gonadal sex steroids. Following this initial response, there is desensitization and downregulation of the GnRH receptor and subsequent inhibition of the HPG axis including loss of natal sex steroids. One of the most important issues to counsel patients about is the potential for a surge in pubertal signs and symptoms that occurs because of the initial agonist action of the medication. Measurement of LH and FSH immediately following the first dose of GnRH agonist will yield an elevation of LH/FSH and gonadal steroids. These should, however, return to low normal or prepubertal levels.

In prepubertal transgender youth who are determined to be good candidates for therapy, GnRH agonists are administered in the early stages of puberty, classified as Tanner stage 2 breast development in natal girls and 4 mL testicular size in natal boys ( Fig. 6.2 A and B ). In Caucasian US youths, this typically occurs at around age 10 years for both boys and girls (data from National Health and Nutrition Examination Survey (NHANES) collected 1988–94), although this has been the subject of some debate. It is important to distinguish central puberty from adrenarche, which is the awakening of the adrenal glands that promotes growth and development at the pilosebaceous units of the skin. Adrenarche is responsible for apocrine odor, axillary hair, acne, and pubic hair. This distinction is particularly important as adrenarche and puberty are often temporally related but are different axes entirely, and adrenarche may precede central puberty by several years. This distinction can be determined by clinical and biochemical assessment by an experienced clinician.

Tanner staging for breast and pubic hair. (A) Female. (B) Male. (By Michal Komorniczak.)

GnRH agonists can also be used in transgender adolescents in late or completed puberty. While generally tolerated, this may lead to perimenopausal symptoms, such as low energy, hot flashes, and decreased libido due to the sudden loss of sex hormones. Linear growth will also be affected for the duration of the blockade; children will be expected to grow at a prepubertal velocity, which is much lower than the sex-steroid–fueled growth spurt of adolescence. In the late pubertal child, GnRH agonist therapy may be appropriate for a natal female who has developed some breast tissue but remains premenarchal or in the natal male who is has enlarged testicles but has not yet developed facial hair or a more angular face shape.

GnRH agonists are available as an intramuscular injection or as a subcutaneous implant. A daily intranasal spray is available but not widely used in this population. Leuprolide is available as a once-monthly or every-3-month injection, while histrelin acetate is available as a subcutaneous implant that releases medication daily. In our clinical practice, we often use the latter given its high level of effectiveness, rapid onset of action, lack of need for repeated injections, and long-term effect. While approved for one year by the Food and Drug Administration (FDA), many patients benefit from a longer duration of use, up to 2 to 3 years in our experience.

Once implemented, GnRH agonist therapy is typically continued until gender-affirming hormones are at desired levels, or until continuing therapy with a GnRH agonist is no longer indicated (e.g. natal male undergoes gonadectomy). Treatment with gender-affirming hormones may require higher doses if not used concomitantly with a GnRH agonist, especially in natal males. With the increased prevalence of gender fluidity, some individuals desire pubertal blockade but do not desire to move forward with gender-affirming hormones and this can be challenging to manage without a clear endpoint of treatment in the setting of adverse effects (e.g. decreasing bone density) associated with not having circulating sex steroids.

Despite having years of experience with GnRH agonists in the central precocious puberty population, in which it has been shown to be safe and effective as well as reversible, little is known about potential long-term effects in the transgender population. It has, however, been shown to be an effective therapy for cessation of puberty in these patients. Regardless, there are specific concerns about the longer-term use of these agonists on bone health, psychological maturation, and long-term adjustment.

Approximately 40% of bone mass accrual occurs during puberty with the increase of sex steroids as one of the major drivers of this process. Children who have early puberty have a higher bone mineral density (BMD) and the corollary is also true: children with delayed puberty have decreased BMD. Long-term treatment with GnRH agonists does not appear to be detrimental. This information, however, should be applied with caution in the transgender population. There has been only one study published looking at the BMD effect of GnRH agonist on a population of treated individuals. This study compared pre- and post-treatment BMD Z-scores at the start of therapy with a GnRH agonist, at the initiation of gender-affirming hormones, and then again at 22 years of age. BMD Z-scores were decreased in both trans men and trans women at the initiation of cross-sex hormone therapy but did increase by the end of the study, although not to baseline for trans women (absolute score was higher). This study was limited by its small sample size. Additionally, the subjects were only on GnRH agonist monotherapy for a limited time, and therefore results of the study cannot be generalized to adolescents who may start therapy in early puberty.

Concern has been raised about the effects of GnRH agonist therapy on brain maturation, particularly as one of the goals of providing puberty suppression is to allow the adolescent time to solidify or clarify their gender identity. There is concern that suppression of sex steroids will inhibit maturation of some of these processes. Currently, there is little evidence to either support or refute this. The working group consensus statement from the American Academy of Pediatrics on the use of GnRH agonists is that there is little evidence to be able to evaluate the impact of GnRH agonist therapy on psychosocial function.